SUMMARY The neuropathology of AD includes fibrillary amyloid ? (A?) in plaques, cerebral amyloid angiopathy (CAA), and hyperphosphorylated tau fibrils in neurofibrillary tangles (NFT). However, the most toxic species are A? and tau oligomers characterized by generic structural ?-sheet secondary structure. These misfolded A? and tau conformers are suitable targets for immunological intervention, although numerous clinical trials thus far have failed due to: 1) autoimmune toxicity; 2) lack of specific concomitant targeting of oligomeric A? and tau species; and 3) Amyloid Related Imaging Abnormalities (ARIA), particularly among apolipoprotein (apo)E4 carriers, thought to be associated with fibrillar vessel amyloid clearance. To overcome these limitations, we developed innovative antibody combining sites (a?ComAb paratopes) that only recognize the dominant ?- sheet secondary structure of misfolded proteins, a generic characteristic of all pathologic oligomers found in neurodegenerative diseases. Our preliminary results show that some a?ComAb combining sites on either IgM or IgG class can, without side effects, penetrate the BBB of an AD Tg mouse model with pre-existing A? and tau pathology, achieve significant cognitive rescue, reduce levels of A? and tau pathological oligomers, and in a CAA AD Tg mouse model (TgSwDI) act without ARIA-like toxicity (both models on murine apoE background). In this project, we will test the hypothesis that a?ComAbs (IgM or IgG), unlike mAbs directed against A? sequences (6E10), can be infused safely and produce modifying therapeutic effects without vascular ARIA-like toxicity in 3xTg and the vascular TgSwDI or APP/PS1dE9 mouse models cross-bred to human apoE2, E3, or E4 backgrounds. Furthermore, we anticipate that the vascular amyloid proteomes of these mice will resemble those that Projects 1 and 2 associate with different apoE backgrounds, treatments, and presence or absence of microhemorrhages. This information is critically needed to elucidate the mechanism associated with ARIA and select a?ComAbs paratopes for future clinical trials. The specific aims are to: 1) Produce and characterize IgM and IgG forms of combining sites (A?ComAb paratopes) that specifically recognize the ?-sheet secondary structures of toxic oligomers. 2) Determine the biochemical and histochemical interaction of the four a?ComAbs from Aim 1 with the brain vasculature of peripherally infused TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds. 3) Determine behavioral, histochemical, and biochemical changes after passive immunotherapy with two A?ComAb paratopes on an IgM and an IgG selected from Aim 2, in 3xTg, Tg APP/PS1dE9, and TgSwDI mice crossed on KI human ApoE2, E3, and E4 backgrounds.